The loss of vision caused by glaucoma results from death of retinal ganglion cells (RGC), whose intraretinal environment consists of interacting processes, some of which promote survival and others that lead toward death. This project studies initial alterations in the balance between life and death of RGC in both experimental models of glaucoma in mice and in the post-mortem ocular tissue of persons with glaucoma. It has identified and will clarify the first steps in RGC death, and will investigate interventions that prevent RGC loss in the second leading cause of worldwide blindness. First, we determine the role of specific connective tissue elements in the sclera that transmit intraocular pressure (IOP)-induced force directly and indirectly into RGC injury. A series of carefully chosen transgenic mouse strains will be studied to identify what alterations in the biomechanical response of the eye to IOP are most likely to either increase or decrease neuronal injury as measured in acute and chronic mouse glaucoma models. Since half of those with open-angle glaucoma suffer RGC loss at normal IOP levels, we will determine candidate molecules and interactions in the eye[unreadable]s support tissues that encourage glaucoma damage at normal IOP. Second, we will determine the extent to which altered capillary function at the optic nerve head contributes to RGC damage, perhaps mediated by tumor necrosis factor alpha and endothelin. Failure of normal vascular nutrition is generally agreed to play a role in glaucoma, but the mechanism(s) of actual damage have not been detailed. Finally, we will dissect how cjun n-terminal kinase participates as an initial signal to start RGC death. Transgenic mice deficient in this molecule will be used to determine the potential therapeutic benefit of eliminating this signal. The project will synthesize some areas of present knowledge about early glaucoma injury to derive a cohesive picture for potential new therapy. Candidate molecules for genetic susceptibility to glaucoma are likely to be identified.